1. Field of the Invention
The present invention relates to novel terephthalamide derivatives and in particular to novel terephthalamide derivatives of the following formula 1, its pharmaceutically acceptable salts as antiviral agents having remarkable inhibitory activities against the proliferation of various viruses including HIV and HBV, and preparing method thereof. ##STR2## Wherein: R.sub.1 and R.sub.2 represent independently one selected from hydrogen atom; phenyl group; benzyl group; C.sub.1 .about.C.sub.6 alkyl group; substituted C.sub.1 .about.C.sub.4 alkyl group in which substituent selected from di(C.sub.1 .about.C.sub.4 alkyl)amino, acetylamino group and heterocycles; C.sub.1 .about.C.sub.5 hydroxyalkyl group; substituted C.sub.1 .about.C.sub.4 hydroxyalkyl group in which one or two suitable substituents selected from phenyl, benzyl, C.sub.1 .about.C.sub.4 hydroxyalkyl and C.sub.1 .about.C.sub.7 alkyl group; C.sub.2 .about.C.sub.6 alkoxyalkyl group; di(C.sub.2 .about.C.sub.6 alkoxy)alkyl group; C.sub.2 .about.C.sub.5 (hydroxyalkoxy)alkyl group; with the proviso that R.sub.1 and R.sub.2 do not simultaneously represent hydrogen atom; in case where either R.sub.1 or R.sub.2 is hydrogen atom, the stereospecificity of (R)- or (S)-type may be represented;
further, R.sub.1 and R.sub.2 may be combined with one or two hetero atoms selected from nitrogen, oxygen and sulfur to form five or six membered heterocycles, wherein the heterocycles may be substituted with one substituent selected from C.sub.1 .about.C.sub.5 alkyl, C.sub.3 .about.C.sub.6 cycloalkyl, C.sub.3 .about.C.sub.5 (hydroxyalkoxy)alkyl, C.sub.2 .about.C.sub.5 hydroxyalkyl, C.sub.1 .about.C.sub.3 alkyl-substituted C.sub.1 .about.C.sub.4 hydroxyalkyl, C.sub.1 .about.C.sub.4 dihydroxyalkyl and C.sub.1 .about.C.sub.3 alkyl-substituted C.sub.1 .about.C.sub.4 dihydroxyalkyl group; PA1 R.sub.3 represents C.sub.1 .about.C.sub.4 alkyl group; PA1 further, the above mentioned alkyl group includes straight or branched alkyl group or cycloalkyl group. PA1 In case where from the above R.sub.1 and R.sub.2, one is hydrogen atom and the other is an C.sub.1 .about.C.sub.3 alkoxy C.sub.1 .about.C.sub.4 alkyl group; di(C.sub.2 .about.C.sub.5 alkoxy) C.sub.1 .about.C.sub.4 alkyl group; 1,3-dioxolan-2-yl-methyl group; tetrahydrofuran-2-yl-methyl group; 2-(morpholin-4-yl)ethyl group; 3-(morpholin-4-yl)propyl group; 2-(piperidin-1-yl)ethyl group; di(C.sub.1 .about.C.sub.3 alkyl) amino C.sub.1 .about.C.sub.3 alkyl group; 2-(acetylamino)ethyl group; 2-hydroxyethyl group; or substituted 2-hydroxyethyl group with one or two suitable substituents selected from phenyl group, benzyl group, C.sub.1 .about.C.sub.3 hydroxyalkyl group and C.sub.1 .about.C.sub.5 alkyl group, PA1 In case where from the above R.sub.1 and R.sub.2, one is C.sub.1 .about.C.sub.3 alkyl group and the other is di(C.sub.1 .about.C.sub.3 alkoxy) C.sub.2 .about.C.sub.3 alkyl group; 1,3-dioxolan-2-yl-methyl group; tetrahydrofuran-2-yl-methyl group; 2-(morpholin-4-yl)ethyl group; 3-(morpholin-4-yl)propyl group; 2-(piperidin-1-yl)ethyl group; 2-hydroxyethyl group; di(C.sub.1 .about.C.sub.3 alkyl)amino C.sub.1 .about.C.sub.3 alkyl group; or 2-(acetylamino)ethyl group, PA1 In case where the above R.sub.1 and R.sub.2 are simultaneously C.sub.1 .about.C.sub.3 alkyl group, hydroxyethyl group or 2-hydroxypropyl group, and PA1 In case where the above R.sub.1 and R.sub.2 are combined with one or two hetero atoms selected from nitrogen, oxygen and sulfur to form heterocycles such as morpholine, thiomorpholine, pyrrolidine, piperidine or piperazine ring, in particularly in the case of piperazine ring it is selectively substituted with hydrogen atom, C.sub.1 .about.C.sub.5 alkyl group, C.sub.3 .about.C.sub.6 cycloalkyl group, C.sub.2 .about.C.sub.5 hydroxyalkyl group, C.sub.2 .about.C.sub.4 dihydroxyalkyl group, C.sub.3 .about.C.sub.5 (hydroxyalkoxy)alkyl group, C.sub.1 .about.C.sub.3 alkyl-substituted C.sub.1 .about.C.sub.4 hydroxyalkyl group, (2R)-3-hydroxy-2-methylpropyl group or (2S)-3-hydroxy-2-methylpropyl group. PA1 In case where R.sub.1 is 2-hydroxyethyl group, while R.sub.2 is hydrogen atom, methyl, ethyl or isopropyl group, PA1 In case where R.sub.1 and R.sub.2 are simultaneously 2-hydroxyethyl, 2-hydroxypropyl, ethyl or isopropyl group, PA1 In case where R.sub.1 is hydrogen atom, while R.sub.2 is a substituted 2-hydroxyethyl group, showing (R)- or (S)-type of stereospecificity, in which a substituent in particular such as methyl, ethyl, isopropyl, phenyl, benzyl or hydroxymethyl group at 1- or 2-position, or substituted 2-hydroxyethyl group in which two substituents in particular such as methyl, ethyl or hydroxymethyl group at 1-position, PA1 In case where R.sub.1 is hydrogen atom or 2-methoxyethyl group, while R.sub.2 is 2-methoxyethyl, 3-methoxypropyl, 3-ethoxypropyl or 3-isopropoxypropyl group, PA1 In case where R.sub.1 is hydrogen atom or methyl group, while R.sub.2 is 2,2-dimethoxyethyl, 2,2-diethoxyethyl, 1,3-dioxolan-2-yl-methyl, tetrahydrofuran-2-yl-methyl, 2-(morpholin-4-yl)ethyl, 3-(morpholin-4-yl)propyl or 2-(piperidin-1-yl)ethyl group, PA1 In case where R.sub.1 is hydrogen atom, methyl or ethyl group, while R.sub.2 is 2-(dimethylamino)ethyl, 2-(diethylamino)ethyl, 3-(dimethylamino)propyl, 3-(diethylamino)propyl or 2-(acetylamino)ethyl group, PA1 In case where R.sub.1 and R.sub.2 are forming heterocycles such as morpholine, thiomorpholine, pyrrolidine, piperidine or piperazine ring, together with nitrogen atom, PA1 In case where R.sub.1 and R.sub.2 are forming a piperazine ring, while the nitrogen atom at 4-position is selectively substituted with methyl, ethyl, isopropyl, cyclopropyl, cyclopentyl, 2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, 2,2-dimethyl-3-hydroxypropyl, (2R)-3-hydroxy-2-methylpropyl, (2S)-3-hydroxy-2-methylpropyl or 2-(2-hydroxyethoxy)ethyl group, and PA1 In particular preferred terephthalamide derivatives of the formula 1, both R.sub.1 and R.sub.2 are the same as defined above, while R.sub.3 is an isopropyl group. PA1 1-N-(2-Hydroxyethyl)carbamoyl!-4-1-3-(isopropylamino)-2-pyridyl!piperazi n-4-yl-carbonyl!benzene (Compound No. 1), PA1 1-N-(3-Hydroxypropyl)carbamoyl!-4-1-3-(isopropylamino)-2-pyridyl!piperaz in-4-yl-carbonyl!benzene (Compound No. 2), PA1 1-N-(4-Hydroxybutyl)carbamoyl!-4-1-3-(isopropylamino)-2-pyridyl!piperazi n-4-yl-carbonyl!benzene (Compound No. 3), PA1 1-N-(5-Hydroxypentyl)carbamoyl!-4-1-3-(isopropylamino)-2-pyridyl!piperaz in-4-yl-carbonyl!benzene (Compound No. 4), PA1 1-N-(2-Hydroxyethyl)-N-methylcarbamoyl!-4-1-3-(isopropylamino)-2-pyridyl !piperazin-4-yl-carbonyl!benzene (Compound No. 5), PA1 1-N-Ethyl-N-(2-hydroxyethyl)carbamoyl!-4-1-3-(isopropylamino)-2-pyridyl! piperazin-4-yl-carbonyl!benzene (Compound No. 6), PA1 1-N-(2-Hydroxyethyl)-N-propylcarbamoyl!-4-1-3-(isopropylamino)-2-pyridyl !piperazin-4-yl-carbonyl!benzene (Compound No. 7), PA1 1-N-(2-Hydroxyethyl)-N-(1-methylethyl)carbamoyl!-4-1-3-(isopropylamino)- 2-pyridyl!piperazin-4-yl-carbonyl!benzene (Compound No. 8), PA1 1-N-Butyl-N-(2-hydroxyethyl)carbamoyl!-4-1-3-(isopropylamino)-2-pyridyl! piperazin-4-yl-carbonyl!benzene (Compound No. 9), PA1 1-N-Benzyl-N-(2-hydroxyethyl)carbamoyl!-4-1-3-(isopropylamino)-2-pyridyl !piperazin-4-yl-carbonyl!benzene (Compound No. 10), PA1 1-N-(2-Hydroxyethyl)-N-phenylcarbamoyl!-4-1-3-(isopropylamino)-2-pyridyl !piperazin-4-yl-carbonyl!benzene (Compound No. 11), PA1 1-N,N-Bis(2-hydroxyethyl)carbamoyl!-4-1-3-(isopropylamino)-2-pyridyl!pip erazin-4-yl-carbonyl!benzene (Compound No. 12), PA1 1-N,N-Diethylcarbamoyl!-4-1-3-(isopropylamino)-2-pyridyl!piperazin-4-yl- carbonyl!benzene (Compound No. 13), PA1 1-N,N-Bis(1-methylethyl)carbamoyl!-4-1-3-(isopropylamino)-2-pyridyl!pipe razin-4-yl-carbonyl!benzene (Compound No. 14), PA1 4-1-3-(Isopropylamino)-2-pyridyl!piperazin-4-yl-carbonyl!-1-(N-methyl-N-p ropylcarbamoyl)benzene (Compound No. 15), PA1 1-N,N-Bis(2-hydroxypropyl)carbamoyl!-4-1-3-(isopropylamino)-2-pyridyl!pi perazin-4-yl-carbonyl!benzene (Compound No. 16), PA1 1-N-2-(2-Hydroxyethoxy)ethyl!carbamoyl!-4-1-3-(isopropylamino)-2-pyridy l!piperazin-4-yl-carbonyl!benzene (Compound No. 17), PA1 1-N-Ethyl-N-(2-hydroxyethyl)carbamoyl!-4-1-3-(ethylamino)-2-pyridyl!pipe razin-4-yl-carbonyl!benzene (Compound No. 18), PA1 1-4-1-3-(Isopropylamino)-2-pyridyl!piperazin-4-yl-carbonyl!benzoyl!piper azine (Compound No. 19), PA1 1-4-1-3-(Isopropylamino)-2-pyridyl!piperazin-4-yl-carbonyl!benzoyl!-4-me thylpiperazine (Compound No. 20), PA1 4-Ethyl-1-4-1-3-(isopropylamino)-2-pyridyl!piperazin-4-yl-arbonyl!benzoy l!piperazine (Compound No. 21), PA1 4-Cyclopentyl-1-4-1-3-(isopropylamino)-2-pyridyl!piperazin-4-yl-carbonyl !benzoyl!piperazine (Compound No. 22), PA1 1-4-1-3-(Isopropylamino)-2-pyridyl!piperazin-4-yl-carbonyl!benzoyl!-4-pr opylpiperazine (Compound No. 23), PA1 1-4-1-3-(Isopropylamino)-2-pyridyl!piperazin-4-yl-carbonyl!benzoyl!-4-(1 -methylethyl)piperazine (Compound No. 24), PA1 4-Cyclopropyl-1-4-1-3-(isopropylamino)-2-pyridyl!piperazin-4-yl-carbonyl !benzoyl!piperazine (Compound No. 25), PA1 4-(2-Hydroxyethyl)-1-4-1-3-(isopropylamino)-2-pyridyl!piperazin-4-yl-car bonyl!benzoyl!piperazine (Compound No. 26), PA1 4-(3-Hydroxypropyl)-1-4-1-3-(isopropylam-ino)-2-pyridyl!piperazin-4-yl-c arbonyl!benzoyl!piperazine (Compound No. 27), PA1 4-(2R)-3-Hydroxy-2-methylpropyl!-1-4-1-3-(isopropylamino)-2-pyridyl!pip erazin-4-yl-carbonyl!benzoyl!piperazine (Compound No. 28), PA1 4-(2S)-3-Hydroxy-2-methylpropyl!-1-4-1-3-(isopropylamino)-2-pyridyl!pip erazin-4-yl-carbonyl!benzoyl!piperazine (Compound No. 29), PA1 4-(2,2-Dimethyl-3-hydroxypropyl)-1-4-1-3-(isopropylamino)-2-pyridyl!pipe razin-4-yl-carbonyl!benzoyl!piperazine (Compound No. 30), PA1 4-(2,3-Dihydroxypropyl)-1-4-1-3-(isopropylamino)-2-pyridyl!piperazin-4-y l-carbonyl!benzoyl!piperazine (Compound No. 31), PA1 4-2-(2-Hydroxyethoxy)ethyl!-1-4-1-3-(isopropylamino)-2-pyridyl!piperazi n-4-yl-carbonyl!benzoyl!piperazine (Compound No. 32), PA1 1-4-1-3-(Ethylamino)-2-pyridyl!piperazin-4-yl-carbonyl!benzoyl!-4-(2-hyd roxyethyl)piperazine (Compound No. 33), PA1 1-N-(1,1-Dimethyl-2-hydroxyethyl)carbamoyl!-4-1-3-(isopropylamino)-2-pyr idyl!piperazin-4-yl-carbonyl!benzene (Compound No. 34), PA1 1-N-(1S)-2-Hydroxy-1-methylethyl!carbamoyl!-4-1-3-(isopropylamino)-2-py ridyl!piperazin-4-yl-carbonyl!benzene (Compound No. 35), PA1 1-N-(1R)-2-Hydroxy-1-methylethyl!carbamoyl!-4-1-3-(isopropylamino)-2-py ridyl!piperazin-4-yl-carbonyl!benzene (Compound No. 36), PA1 1-N-(2-Hydroxy-1-methylethyl)carbamoyl!-4-1-3-(isopropylamino)-2-pyridyl !piperazin-4-yl-carbonyl!benzene (Compound No. 37), PA1 1-N-(1S)-2-Hydroxy-1-(1-methylethyl)ethyl!carbamoyl!-4-1-3-(isopropylam ino)-2-pyridyl!piperazin-4-yl-carbonyl!benzene (Compound No. 38), PA1 1-N-(1R)-2-Hydroxy-1-(1-methylethyl)ethyl!carbamoyl!-4-1-3-(isopropylam ino)-2-pyridyl!piperazin-4-yl-carbonyl!benzene (Compound No. 39), PA1 1-N-2-Hydroxy-1-(1-methylethyl)ethyl!carbamoyl!-4-1-3-(isopropylamino)- 2-pyridyl!piperazin-4-yl-carbonyl!benzene (Compound No. 40), PA1 1-N-(1S)-1-Ethyl-2-hydroxyethyl!carbamoyl!-4-1-3-(isopropylamino)-2-pyr idyl!piperazin-4-yl-carbonyl!benzene (Compound No. 41), PA1 1-N-(1R)-1-Ethyl-2-hydroxyethyl!carbamoyl!-4-1-3-(isopropylamino)-2-pyr idyl!piperazin-4-yl-carbonyl!benzene (Compound No. 42), PA1 1-N-(1-Ethyl-2-hydroxyethyl)carbamoyl!-4-1-3-(isopropylamino)-2-pyridyl! piperazin-4-yl-carbonyl!benzene (Compound No. 43), PA1 1-N-(1S)-2-Hydroxy-1-(2-methylpropyl)ethyl!carbamoyl!-4-1-3-(isopropyla mino)-2-pyridyl!piperazin-4-yl-carbonyl!benzene (Compound No. 44), PA1 1-N-(1R)-2-Hydroxy-1-(2-methylpropyl)ethyl!carbamoyl!-4-1-3-(isopropyla mino)-2-pyridyl!piperazin-4-yl-carbonyl!benzene (Compound No. 45), PA1 1-N-(1S)-2-Hydroxy-1-(1-methylpropyl)ethyl!carbamoyl!-4-1-3-(isopropyla mino)-2-pyridyl!piperazin-4-yl-carbonyl!benzene (Compound No. 46), PA1 1-N-(1S)-1-(Cyclohexylmethyl)-2-hydroxyethyl!carbamoyl!-4-1-3-(isopropy lamino)-2-pyridyl!piperazin-4-yl-carbonyl!benzene (Compound No. 47), PA1 1-N-(1S)-2-Hydroxy-1-phenylethyl!carbamoyl!-4-1-3-(isopropylamino)-2-py ridyl!piperazin-4-yl-carbonyl!benzene (Compound No. 48), PA1 1-N-(1R)-2-Hydroxy-1-phenylethyl!carbamoyl!-4-1-3-(isopropylamino)-2-py ridyl!piperazin-4-yl-carbonyl!benzene (Compound No. 49), PA1 1-N-(1S)-1-Benzyl-2-hydroxyethyl!carbamoyl!-4-1-3-(isopropylamino)-2-py ridyl!piperazin-4-yl-carbonyl!benzene (Compound No. 50), PA1 1-N-(1R)-1-Benzyl-2-hydroxyethyl!carbamoyl!-4-1-3-(isopropylamino)-2-py ridyl!piperazin-4-yl-carbonyl!benzene (Compound No. 51), PA1 1-N-Bis(hydroxymethyl)methyl!carbamoyl!-4-1-3-(isopropylamino)-2-pyridy l!piperazin-4-yl-carbonyl!benzene (Compound No. 52), PA1 1-N-1,1-Bis(hydroxymethyl)ethyl!carbamoyl!-4-1-3-(isopropylamino)-2-pyr idyl!piperazin-4-yl-carbonyl!benzene (Compound No. 53), PA1 1-N-1,1-Bis(hydroxymethyl)propyl!carbamoyl!-4-1-3-(isopropylamino)-2-py ridyl!piperazin-4-yl-carbonyl!benzene (Compound No. 54), PA1 1-N-Tris(hydroxymethyl)methyl!carbamoyl!-4-1-3-(isopropylamino)-2-pyrid yl!piperazin-4-yl-carbonyl!benzene (Compound No. 55), PA1 1-N-(2S)-2-Hydroxypropyl!carbamoyl!-4-1-3-(isopropylamino)-2-pyridyl!pi perazin-4-yl-carbonyl!benzene (Compound No. 56), PA1 1-N-(2R)-2-Hydroxypropyl!carbamoyl!-4-1-3-(isopropylamino)-2-pyridyl!pi perazin-4-yl-carbonyl!benzene (Compound No. 57), PA1 1-N-(2-Hydroxypropyl)carbamoyl!-4-1-3-(isopropylamino)-2-pyridyl!piperaz in-4-yl-carbonyl!benzene (Compound No. 58), PA1 1-N-(2-Hydroxy-2-phenylethyl)carbamoyl!-4-1-3-(isopropylamino)-2-pyridyl !piperazin-4-yl-carbonyl!benzene (Compound No. 59), PA1 1-N-(2,3-Dihydroxypropyl)carbamoyl!-4-1-3-(isopropylamino)-2-pyridyl!pip erazin-4-yl-carbonyl!benzene (Compound No. 60), PA1 4-1-3-(Isopropylamino)-2-pyridyl!piperazin-4-yl-carbonyl!-1-N-(2-methoxy ethyl)carbamoyl!benzene (Compound No. 61), PA1 1-N,N-Bis(2-methoxyethyl)carbamoyl!-4-1-3-(isopropylamino)-2-pyridyl!pip erazin-4-yl-carbonyl!benzene (Compound No. 62), PA1 4-1-3-(Isopropylamino)-2-pyridyl!piperazin-4-yl-carbonyl!-1-N-(2-methoxy -1-methylethyl)carbamoyl!benzene (Compound No. 63), PA1 4-1-3-(Isopropylamino)-2-pyridyl!piperazin-4-yl-carbonyl!-1-N-(3-methoxy propyl)carbamoyl!benzene (Compound No. 64), PA1 1-N-(3-Ethoxypropyl)carbamoyl!-4-1-3-(isopropylamino)-2-pyridyl!piperazi n-4-yl-carbonyl!benzene (Compound No. 65), PA1 1-N-(3-Isopropoxypropyl)carbamoyl!-4-1-3-(isopropylamino)-2-pyridyl!pipe razin-4-yl-carbonyl!benzene (Compound No. 66), PA1 4-1-3-(Isopropylamino)-2-pyridyl!piperazin-4-yl-carbonyl!-1-N-3-(vinylo xy)propyl!carbamoyl!benzene (Compound No. 67), PA1 1-N-(2,2-Dimethoxyethyl)-N-methylcarbamoyl!-4-1-3-(isopropylamino)-2-pyr idyl!piperazin-4-yl-carbonyl!benzene (Compound No. 68), PA1 1-N-(2,2-Dimethoxyethyl)carbamoyl!-4-1-3-(isopropylamino)-2-pyridyl!pipe razin-4-yl-carbonyl!benzene (Compound No. 69), PA1 1-N-(2,2-Diethoxyethyl)carbamoyl!-4-1-3-(isopropylamino)-2-pyridyl!piper azin-4-yl-carbonyl!benzene (Compound No. 70), PA1 1-N-(1,3-Dioxolan-2-yl)methyl!-N-methylcarbamoyl!-4-1-3-(isopropylamino )-2-pyridyl!piperazin-4-yl-carbonyl!benzene (Compound No. 71), PA1 4-1-3-(Isopropylamino)-2-pyridyl!piperazin-4-yl-carbonyl!-1-N-(tetrahyd rofuran-2-yl)methyl!carbamoyl!benzene (Compound No. 72), PA1 4-1-3-(Isopropylamino)-2-pyridyl!piperazin-4-yl-carbonyl!-1-N-(2R)-tet rahydrofuran-2-yl!methyl!carbamoyl!benzene (Compound No. 73), PA1 4-1-3-(Isopropylamino)-2-pyridyl!piperazin-4-yl-carbonyl!-1-N-(2S)-tet rahydrofuran-2-yl!methyl!carbamoyl!benzene (Compound No. 74), PA1 1-N-(Furan-2-yl)methyl!carbamoyl!-4-1-3-(isopropylamino)-2-pyridyl!pipe razin-4-yl-carbonyl!benzene (Compound No. 75), PA1 4-1-3-(Isopropylamino)-2-pyridyl!piperazin-4-yl-carbonyl!-1-(morpholin-4- yl-carbonyl)benzene (Compound No. 76), PA1 4-1-3-(Isopropylamino)-2-pyridyl!piperazin-4-yl-carbonyl!-1-(thiomorpholi n-4-yl-carbonyl)benzene (Compound No. 77), PA1 4-1-3-(Isopropylamino)-2-pyridyl!piperazin-4-yl-carbonyl!-1-(thiazolidin- 3-yl-carbonyl)benzene (Compound No. 78), PA1 4-1-3-(Isopropylamino)-2-pyridyl!piperazin-4-yl-carbonyl!-1-N-2-(morpho lin-4-yl)ethyl!carbamoyl!benzene (Compound No. 79), PA1 4-1-3-(Isopropylamino)-2-pyridyl!piperazin-4-yl-carbonyl!-1-N-3-(morpho lin-4-yl)propyl!carbamoyl!benzene (Compound No. 80), PA1 4-1-3-(Isopropylamino)-2-pyridyl!piperazin-4-yl-carbonyl!-1-N-2-(piperi din-1-yl)ethyl!carbamoyl!benzene (Compound No. 81), PA1 4-1-3-(Isopropylamino)-2-pyridyl!piperazin-4-yl-carbonyl!-1-N-2-(pyrrol idin-1-yl)ethyl!carbamoyl!benzene (Compound No. 82), PA1 1-N-2-(Dimethylamino)ethyl!carbamoyl!-4-1-3-(isopropylamino)-2-pyridyl! piperazin-4-yl-carbonyl!benzene (Compound No. 83), PA1 1-N-2-(Dimethylamino)ethyl!-N-methylcarbamoyl!-4-1-3-(isopropylamino)-2 -pyridyl!piperazin-4-yl-carbonyl!benzene (Compound No. 84), PA1 1-N-2-(Dimethylamino)ethyl!-N-ethylcarbamoyl!-4-1-3-(isopropylamino)-2- pyridyl!piperazin-4-yl-carbonyl!benzene (Compound No. 85), PA1 1-N-2-(Diethylamino)ethyl!carbamoyl!-4-1-3-(isopropylamino)-2-pyridyl!p iperazin-4-yl-carbonyl!benzene (Compound No. 86), PA1 1-N-2-(Diethylamino)ethyl!-N-methylcarbamoyl!-4-1-3-(isopropylamino)-2- pyridyl!piperazin-4-yl-carbonyl!benzene (Compound No. 87), PA1 1-N-2-(Diethylamino)ethyl!-N-ethylcarbamoyl!-4-1-3-(isopropylamino)-2-p yridyl!piperazin-4-yl-carbonyl!benzene (Compound No. 88), PA1 1-N-3-(Dimethylamino)propyl!carbamoyl!-4-1-3-(isopropylamino)-2-pyridyl !piperazin-4-yl-carbonyl!benzene (Compound No. 89), PA1 1-N-3-(Dimethylamino)propyl!-N-methylcarbamoyl!-4-1-3-(isopropylamino)- 2-pyridyl!piperazin-4-yl-carbonyl!benzene (Compound No. 90), PA1 1-N-3-(Diethylamino)propyl!carbamoyl!-4-1-3-(isopropylamino)-2-pyridyl! piperazin-4-yl-carbonyl!benzene (Compound No. 91), PA1 1-N-2-(Acetylamino)ethyl!carbamoyl!-4-1-3-(isopropylamino)-2-pyridyl!pi perazin-4-yl-carbonyl!benzene (Compound No. 92), PA1 4-1-3-(Isopropylamino)-2-pyridyl!piperazin-4-yl-carbonyl!-1-(piperidin-1- yl-carbonyl)benzene (Compound No. 93), PA1 4-1-3-(Isopropylamino)-2-pyridyl!piperazin-4-yl-carbonyl!-1-(pyrrolidin-1 -yl-carbonyl)benzene (Compound No. 94). PA1 R.sub.4 represents hydrogen atom, C.sub.1 .about.C.sub.5 alkyl group, C.sub.3 -C.sub.6 cycloalkyl group, C.sub.2 .about.C.sub.5 hydroxyalkyl group, C.sub.2 .about.C.sub.4 dihydroxyalkyl group, C.sub.3 .about.C.sub.5 (hydroxyalkoxy)alkyl group, C.sub.1 .about.C.sub.3 alkyl-substituted C.sub.1 .about.C.sub.4 hydroxyalkyl group, (2R)-3-hydroxy-2-methylpropyl or (2S)-3-hydroxy-2-methylpropyl group; PA1 X represents halogen atom.
2. Description of the Prior Art
Worldwide, about 300 million people are infected with hepatitis B virus(hereinafter referred to as "HBV"), one of the main viruses causing hepatitis and prolonged infection has been associated with cirrhosis and hepatocellular carcinoma. Hitherto, many researcher have focused on the HBV relationship with liver diseases and its molecular-biological characteristics. Some vaccines have been developed to prevent infection but no effective therapy exists for treating hepatitis B infection.
In the past years, it was reported that some nucleoside compounds, which have been mainly developed as an anti-AIDS(Acquired Immune Deficiency Syndrome) agent, are effective HBV inhibitors J. Org. Chem., 1992, Vol. 57, 2217!. However, these nucleoside compounds as effective drugs against viral hepatitis B have proven to be undesirable due to high costs of drugs, adverse reactions and toxic effects.
Under such circumstances, there is urgent need for the development of hepatitis B drug having remarkable antiviral activities against HBV as a non-nucleoside compound. Recently, quinolones European unexamined patent No. 563732 and No. 563734! and iridoids Korean unexamined patent No. 94-1886! have been reported to have anti HBV activity but no significant development progress has been noticeable.
To overcome the side effects and toxicities of the conventional drugs and develop some effective non-nucleoside compounds having remarkable antiviral activities against HBV, the inventor et al. have carried out intensive studies. As a result, the inventors have completed this invention wherein terephthalamide derivatives of non-nucleoside compounds with specific structure of the above formula 1 have been found to have potent inhibitory activities against the proliferation of HBV including human immunodeficiency virus(hereinafter referred to as "HIV") and other viruses.
For example, HBV is a virus different from HIV but during proliferation, they have common replication courses, i.e., a reverse transcription step and the resulting RNA template of RNA-DNA hybrid is degraded. Since terephthalamide derivatives according to the present invention of the formula 1, have mechanism to inhibit such proliferation course, it may be developed as effective inhibitor against the proliferation of various viruses including HBV and HIV.